Proliferative vitreoretinopathy (PVR) is caused by membrane formation along the surface of the retina. We have examined the hypothesis that a growth- stimulating "vitreous microenvironment" (VME) occurs during PVR, which promotes the growth of cells within the membrane on the retina. Our longterm goal is to apply knowledge about the VME to the development of new predictive assays and therapeutic modalities for PVR. During the past grant period, we have demonstrated that; (1) the VME becomes "growth- stimulatory" during PVR; (2) this transformation can be measured in terms of two assays (one to quantify infiltrating cells by flow cytometry and one to quantify "aggregate," soluble, growth promoting activity by bioassay); and (3) the magnitude of this transformation, as measured by these two assays, predicts the development of traction retinal detachment (TRD) weeks later. Experiments described in the current proposal will differentiate between two major competing hypotheses: (a) the VME actually regulates PVR severity by promoting membrane growth; or the alternative, (b) the VME merely reflects growth activity within the eye, but the VME itself does not regulate the growth of the membrane. The following specific aim will evaluate these two hypotheses in both animal models and human eyes: (1) determine the mechanisms by which elevated growth-stimulating activity in the VME during experimental PVR promotes the growth of the preretinal membrane; (2) determine how two different therapies that prevent TRD in animal models of PVR differentially impact the VME and the preretinal membrane; (3) test the hypothesis that the risk for developing tractional retinal detachment in humans with PVR can be predicted by the level of growth-stimulating activity in the VME.